Abstract
Retinitis pigmentosa and related photoreceptor dystrophies (RPRPD) are rare retinal diseases caused by hereditary gene mutations resulting in photoreceptor death, followed by vision loss. While numerous genes involved in these diseases have been identified, many cases have still not been associated with any gene, indicating that new mechanisms may be involved in the pathogenesis of these photoreceptor dystrophies. Many genes associated with RPRPD regulate photoreceptor specification and maturation in the developing retina. Since retinal development begins with a population of equivalent, proliferating retinal progenitor cells (RPCs) having a specific “competence” in generating all types of retinal neurons, including cone and rod photoreceptors, we tested the epigenetic changes in promoters of genes required for photoreceptor development and genes associated with RPRPD during RPC differentiation into cone and rod photoreceptors. We found that promoters of many of these genes are epigenetically repressed in RPCs but have no epigenetic restrictions in photoreceptors. Our findings also suggest that DNA methylation as an epigenetic mark, and DNA demethylation as a process, are more important than other epigenetic marks or mechanisms in the pathogenesis of these diseases. Most notably, irregularities in the DNA demethylation process during the RPC-to-photoreceptor transition may significantly contribute to retinitis pigmentosa (RP) pathogenesis since genes with hypermethylated promoters in RPCs account for at least 40% of autosomal recessive RP cases and at least 30% of autosomal dominant RP cases. Thus, we proposed an epigenetic model according to which unsuccessful demethylation of regulatory sequences (e.g., promoters, enhancers) of genes required for photoreceptor development, maturation, and function during the RPC-to-photoreceptor transition may reduce or even eliminate their activity, leading to RPRPD without any inheritable mutations in these genes.
Highlights
Retinitis pigmentosa (RP), cone and cone-rod dystrophy (CCRD), congenital stationary night blindness (CSNB), Leber congenital amaurosis (LCA), and juvenile macular degenerations (MD; e.g., Stargardt disease and Best vitelliform macular dystrophy) are characterized by progressive rod and/or cone photoreceptor loss resulting in poor vision or even blindness (Hartong et al, 2006; Zeitz et al, 2015; Altschwager et al, 2017; Tsang and Sharma, 2018; Gill et al, 2019)
Since DNA methylation and other permissive and repressive epigenetic marks may contribute to the pathogenesis of retinitis pigmentosa (RP), CCRD, CSNB, LCA, and MD, we performed in this study an in-depth analysis of epigenetic states of promoters of all known genes involved in photoreceptor development, function, and pathology during the retinal progenitor cells (RPCs)-to-photoreceptor transition to collect evidence supporting this hypothesis
We studied promoters of 1) 83 genes involved in retinitis pigmentosa - RP, 2) 32 genes involved in cone and cone-rod dystrophy—CCRD, 3) 13 genes involved in congenital stationary night blindness—CSNB, 4) 25 genes involved in Leber congenital amaurosis - LCA, and 5) 17 genes involved in juvenile macular degeneration—MD (Supplementary Data S1 and S2)
Summary
Retinitis pigmentosa (RP), cone and cone-rod dystrophy (CCRD), congenital stationary night blindness (CSNB), Leber congenital amaurosis (LCA), and juvenile macular degenerations (MD; e.g., Stargardt disease and Best vitelliform macular dystrophy) are characterized by progressive rod and/or cone photoreceptor loss resulting in poor vision or even blindness (Hartong et al, 2006; Zeitz et al, 2015; Altschwager et al, 2017; Tsang and Sharma, 2018; Gill et al, 2019). Since many RP, CCRD, CSNB, LCA, and MD cases have not been associated with any gene yet and epigenetic repression of genes critical for photoreceptor specification and maturation/function may lead to these diseases, we analyzed DNA methylome and chromatin states in the promoters of genes involved in these processes using the results of our analysis above. Genome-wide DNA methylation/demethylation pathway analysis revealed that DNMTs have global activity, methylating DNA wherever possible until something interferes with them, while TETs have a local effect, demethylating regulatory sequences (e.g., promoters, enhancers) and stay there to safeguard from de novo methylation by DNMT enzymes (Rasmussen et al, 2015; Wiehle et al, 2016; Verma et al, 2018; Lopez-Moyado et al, 2019; Charlton et al, 2020) Since both families establish DNA methylation patterns in cells, we evaluated the expression of the corresponding genes in: 1) human embryonic retinas using GSE87042 RNA-seq data; 2) developing mouse retinas using GSE101986 RNA-seq data; 3) mature rod and cone photoreceptors using GSE72550 RNA-seq data; and 4) RPCs using our published data (Dvoriantchikova et al, 2019a). Since obtaining human retinal biopsy samples is impossible in the near future, in vitro and in vivo animal models should be used to study photoreceptor dystrophies as epigenetic disorders
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